Nuclear Interleukin-33 Is Generally Expressed in Resting Endothelium but Rapidly Lost upon Angiogenic or Proinflammatory Activation

Küchler, Axel M.; Pollheimer, Jürgen; Balogh, Johanna; Sponheim, Jon; Manley, Linda; Sørensen, Dag R.; Angelis, Paula M. De; Scott, Helge; Haraldsen, Guttorm

doi:10.2353/ajpath.2008.080014

Cited by 196 publications

(223 citation statements)

References 45 publications

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“…34,35 Whole lung levels of IL-33 peaked on day 7 after conidia challenge, but circulating levels of IL-33 were less than the limits of detection in the fungal asthma model. However, IL-33 normally resides in the cell nucleus 45,46 and inflammatory events leading to cell necrosis allow its release. 33 Anaphylactic shock appears to be one human condition that is characterized by the release of major amounts of IL-33 into the circulatory system.…”

Section: Discussionmentioning

confidence: 99%

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Ramaprakash

Shibata

Duffy³

et al. 2011

The American Journal of Pathology

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IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.

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Section: Discussionmentioning

confidence: 99%

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Ramaprakash

Shibata

Duffy³

et al. 2011

The American Journal of Pathology

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“…However, intranuclear retention may be used by cells to prevent the release of other pro-inflammatory mediators following cell death. For example, IL-33 (IL-1F11), an immunomodulatory member of the IL-1 cytokine family [30], is intranuclear in resting endothelial cells in vivo [31,32]. Intranuclear IL-33 associates with chromatin to regulate transcription [33,34], but this interaction could also allow IL-33 retention following endothelial cell death.…”

Section: Discussionmentioning

confidence: 99%

Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

2009

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Sterile inflammation is a host response to tissue injury that is mediated by damage-associated molecular patterns released from dead cells. Sterile inflammation worsens damage in a number of injury paradigms. The pro-inflammatory cytokine IL-1a is reported to be a damage-associated molecular pattern released from dead cells, and it is known to exacerbate brain injury caused by stroke. In the brain, IL-1a is produced by microglia, the resident brain macrophages. We found that IL-1a is actively trafficked to the nuclei of microglia, and hence tested the hypothesis that trafficking of IL-1a to the nucleus would inhibit its release following necrotic cell death, limiting sterile inflammation. Microglia subjected to oxygenglucose deprivation died via necrosis. Under these conditions, microglia expressing nuclear IL-1a released significantly less IL-1a than microglia with predominantly cytosolic IL-1a. The remaining IL-1a was immobilized in the nuclei of the dead cells. Thus, nuclear retention of IL-1a may serve to limit inflammation following cell death.Key words: IL-1a . Microglia . Necrosis . Nuclear retention . Sterile inflammation Supporting Information available online IntroductionSterile inflammation is a host response to tissue injury that can exacerbate the initial insult [1]. Intracellular molecules released from necrotic cells act as damage-associated molecular patterns (DAMP), signaling to the innate immune system that tissue injury has occurred [2]. IL-1a, a pro-inflammatory member of the IL-1 cytokine family [3], has recently been identified as a DAMP released from necrotic cells [4]. In addition, necrotic cell DAMP are reported to stimulate IL-1a production by immune cells, which further exacerbates sterile inflammation [1]. Experimental stroke in rodents elicits an inflammatory response that markedly exacerbates brain injury [5]. IL-1a is a key contributor to this injury, and its genetic ablation (along with IL-1b, a related cytokine) causes a 70% reduction in the brain injury caused by stroke [6].In the brain after injury (e.g. stroke, hemorrhage, trauma), IL-1 family cytokines are produced by microglia, the resident brain macrophages [7]. IL-1a is produced in the cytosol as a 31-kDa protein that, following release from necrotic cells, activates the type I IL-1 receptor on responsive cell membranes [8,9]. The Nterminal domain of IL-1a contains a nuclear localization sequence, which mediates active nuclear import [10,11]. IL-1a has been reported to act within the nucleus to regulate cytokine transcription and RNA splicing [12,13]. In this study we sought to test the hypothesis that IL-1a nuclear import also inhibits IL-1a release following necrotic cell death. We report that IL-1a nuclear import and intranuclear retention reduce IL-1a release from necrotic microglia. Thus, IL-1a nuclear retention by necrotic cells may inhibit injury-induced inflammation. Results IL-1a nuclear localization is inhibited at high cell densityTo investigate the effects of IL-1a nuclear localization on IL-1a release after ne...

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“…IL-33 is a new member of the IL-1 family and recent publications imply that vascular endothelial cells are the dominant IL-33-expressing cell population in vivo (Küchler et al, 2008). Recent data suggest that IL-33 promotes angiogenesis and endothelial permeability involved in tumorigenesis (Choi et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Serum IL-33 as a Diagnostic and Prognostic Marker in Non-small Cell Lung Cancer

Liang-an

Yu²,

Zhang³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Nuclear Interleukin-33 Is Generally Expressed in Resting Endothelium but Rapidly Lost upon Angiogenic or Proinflammatory Activation

Abstract: Interleukin (IL)-

Cited by 196 publications

References 45 publications

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

Serum IL-33 as a Diagnostic and Prognostic Marker in Non-small Cell Lung Cancer

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